The unifying hypothesis of the NU SCOR continues to be that genetic variation resulting in hyperandrogenemia causes many of the phenotypic features of PCOS by prenatal androgen programming as well as by continued androgen excess in the adult. The following exciting findings from the initial award period support this hypothesis: 1) a major PCOS susceptibility variant, allele 8 (A8) of D19S884, has been mapped to intron 55 of the fibrillin-3 gene, 2) a distinctive metabolic phenotype, hepatic insulin resistance, is associated with the A8 variant;3) prenatal androgen excess causes LH secretory defect, insulin resistance and increased visceral adiposity, all features of PCOS, in animal models;4) LH secretory changes result from decreased expression of hypothalamic potassium sensitive ATP (KATP) channels that modulate gonadotropin releasing hormone (GnRH) secretion. Prenatal androgen exposure induces resistance to estrogen-mediated increases in KATP channel expression that occur through induction of progesterone receptor expression. 5) Prenatal androgens also decrease expression of KATP channels in pancreatic Beta-cells providing one potential mechanism for the metabolic phenotype. Project 1 will investigate the mechanisms of hepatic insulin resistance associated with the A8 genotype in women with PCOS including the role of androgens. Potential sex-specific effects will be investigated in male first degree relatives with A8 genotype. Project 2 will investigate the impact of variation in D19S884 on parameters of glycemic control and pregnancy outcome in mothers and their infants from a large multiethnic population, including the possible association of D19S884 allelic variation with androgen levels in this non-PCOS population. In addition, the potential role of fibrillin-3 itself in the pathogenesis of PCOS will be investigated by examining the TGFBeta signaling pathway, which is potentially modulated by this molecule. Project 3 is a new project that will investigate the cellular and molecular mechanisms of androgen action on pancreatic Beta-cells. Project 4 will pursue the mechanisms that may mediate androgen programming of the distinctive metabolic phenotype associated with A8, in particular, the hypothesis androgen exposure produces the metabolic defects of PCOS by programming resistance to estrogen's metabolic actions in the brain or periphery.